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Transcriptional regulation of retinal mitochondrial function and cell cycle

视网膜线粒体功能和细胞周期的转录调控

基本信息

批准号：
9439898
负责人：
Ross Anthony Poche
金额：
$ 11.49万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9439898
关键词：
Apoptosis Bioenergetics Blindness Brain CCNE1 gene Candidate Disease Gene Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Cycle Stage Cell Proliferation Cell physiology Cells ChIP-seq Citric Acid Cycle Cobalamin Coupled Couples Coupling Cyclin D1 Data Defect Development Disease Drug Targeting Electroporation Ensure Equilibrium Exhibits Gene Targeting Genes Genetic Genetic Transcription Genomics Goals Histologic Homocystinuria Instruction Knock-out Knockout Mice Lead Length Link Malignant Neoplasms Microscopy Mitochondria Molecular Monitor Morphology Mutate Names Neurodevelopmental Disorder Neuronal Differentiation Nuclear Oxidative Stress Patients Phase Transition Phenocopy Phenotype Play Process Production Proteins Reactive Oxygen Species Regulation Replacement Therapy Respiration Retina Retinal Retinal Degeneration Rodent Role S Phase Supplementation Testing Therapeutic Intervention Tissues Transcriptional Regulation Vitamin B 12 cell growth citrate carrier cohort design developmental disease embryonic stem cell experimental study extracellular fly gain of function human disease imaging modality in utero in vivo interdisciplinary approach malignant retina neoplasm metabolic profile methylmalonic aciduria migration mitochondrial dysfunction mutant novel novel anticancer drug overexpression pluripotency promoter public health relevance retinal progenitor cell retinogenesis transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Retinogenesis requires a tightly controlled balance of retinal progenitor cell (RPC) proliferation and differentiation. Deregulation of this mechanism often results in profound neuro-developmental disorders or cancer. Our long term goal is to elucidate the transcriptional mechanisms coupling RPC cell cycle regulation to neuronal differentiation. In this proposal, experiments will define the role of the transcriptional regulato Ronin (Thap11) in retinogenesis. Ronin was identified recently as a novel embryonic stem cell (ESC) pluripotency factor, influencing ESC proliferation and growth. Ronin is also expressed throughout the developing brain and retina, but its role in these tissues is unknown. In preliminary studies, we have found that Ronin mutant retinae phenocopy the Cyclin D1 null mice thereby implicating Ronin as a regulator of the cell cycle G1 to S-phase transition. However, analysis of preliminary Ronin retinal ChIP-seq data showed enrichment for mitochondrial genes rather than cell cycle machinery. Recently, mitochondria have emerged as critical regulators of the G1 to S-phase transition in both flies and rodents by promoting Cyclin E activity and entry into S-phase. Therefore, we hypothesize that Ronin influences the RPC cell cycle by directly regulating genes required for proper mitochondrial function and promotion of S-phase entry. To test this hypothesis, we have assembled a team with diverse expertise, to facilitate a synergistic, multi- disciplinary approach using genetic loss- and gain-of-function experiments, metabolic profiling, live retinal microscopy and genomics. Upon completion of this proposal, we expect that we will have identified a new transcriptional mechanism that couples mitochondrial function to cell cycle progression in RPCs. This deeper understanding of the transcriptional regulation of multipotent, proliferative RPCs will ultimately inform efficacious strategies for retinal cell replacement therapies as well as novel cancer drug targets functioning at the interface of mitochondrial bioenergetics and the cell cycle.

描述（由申请人提供）：视网膜发生需要严格控制视网膜祖细胞（RPC）增殖和分化的平衡。这种机制的失调通常会导致严重的神经发育障碍或癌症。我们的长期目标是阐明 RPC 细胞周期调节与神经元分化耦合的转录机制。在该提案中，实验将确定转录调节因子 Ronin (Thap11) 在视网膜发生中的作用。 Ronin 最近被鉴定为一种新型胚胎干细胞 (ESC) 多能性因子，可影响 ESC 增殖和生长。 Ronin 也在整个发育中的大脑和视网膜中表达，但其在这些组织中的作用尚不清楚。在初步研究中，我们发现 Ronin 突变视网膜表型与 Cyclin D1 缺失小鼠相似，从而暗示 Ronin 作为细胞周期 G1 到 S 相转变的调节者。然而，对 Ronin 视网膜 ChIP-seq 数据的初步分析显示，线粒体基因富集，而不是细胞周期机制。最近，线粒体通过促进细胞周期蛋白 E 活性和进入 S 期，成为果蝇和啮齿动物 G1 到 S 期转变的关键调节因子。因此，我们假设 Ronin 通过直接调节线粒体正常功能和促进 S 期进入所需的基因来影响 RPC 细胞周期。为了检验这一假设，我们组建了一支具有不同专业知识的团队，利用遗传功能丧失和功能获得实验、代谢分析、活体视网膜显微镜和基因组学来促进协同、多学科的方法。完成这项提案后，我们预计我们将确定一种新的转录机制，将线粒体功能与 RPC 中的细胞周期进程耦合起来。对多能、增殖性 RPC 转录调控的更深入理解将最终为视网膜细胞替代疗法以及在线粒体生物能学和细胞周期界面发挥作用的新型癌症药物靶点提供有效的策略。